Process for producing delta 9, 11-7-ketosteroids



United States Patent BRQCESS. FOR rnonucmc. M m-Karo- STEROIDS 'Leopold-Ruzickag l-Ians Heusser, and-'Gskar Jeger, Zurich,

. Switze'rland,:.assignors toaCiba Pharmaceutical Products, Inc.,Summit, N. J.

3 Claims. (Cl. 260-3971) :The presentainventionsist concerned 1=withaanewtprocess leading tonnewccompounds which rmake .ait; possibletosynthesize therapeutically active steroids containing oxygen in the11position.

The steroids with oxygen in ll-position are of great importance. Animportant representative of this class of compounds is for examplecortisone, A -3,11,20-trioxo-17a,21-dihydroxy-pregnene. The hithertoknown processes for the synthetic production of such steroids used asstarting materials desoxycholic acid and its derivatives, that is to saycompounds which possess a hydroxyl group in 12-position. It has beenshow however that the transfer of oxygen from the 12- to the ll-positionis a very tedious process requiring several operations. In addition thedesoxycholic acid used as starting material is only obtainable inrelatively limited quantity, so that for example it is practicallyimpossible to manufacture the cortisone required in therapy insuflicient quantity by this method. A requirement therefore exists fornew sources for the manufacture of this medicament. The easily availablesterols, such as ergosterol, stigmasterol or sitosterol, but moreespecially cholesterol, have indeed for many years been importantstarting materials for the production of sex hormones. They have howeverhitherto been without importance for the production of compounds withoxygen in the ll-position of the intact steroid structure.

The present invention is based on the observation that by starting fromthe above-mentioned sterols or conversion products thereof, compounds ofthe steroid series with oxygen in the ll-position can be obtained when aA -steroid is treated in stages with an agent capable of introducingoxygen, the resultant 9,11-oxido compound is isomerized, and theoxo-group in 7-position of the resultant 7,11-dioxo-steroid is removedby reduction.

The process is illustrated by the following diagram of partial formulae:

An object of the present invention are A -7-oxosteroids. These compoundsare new and are intended for use as intermediate products for thepreparation of ll-oxo-steroids and ll-hydroxy-steroids. Thus, e. g.,

:pregnane, androstane and: e'tioc holane. the aforementioned doublebonds, 'thestarting mate'rials Eat-tented Oct.-.23,,;1.9,56

ice

the present invention is a step in the preparation of themethyl-3u-acetoxy-l 1=oxo ch0lanate i (see e. g. Example 5. ofcopendingapplication -S. N.i'261,58l,"?filed on even idateherewith).which is.a :recognized and well: known intermediate for theproduction-of Lt-he highly active' hormone 1Ldehydro-eorticosterone (cf.'Wettstein &' Meystre: Helv. Chim. Acta, vol.-.3(),'-.pp.- 1262-1265(1947) Another object of-theinvention -isa process for the manufactureof A -7-oxo-steroids. It comprises' the reaction of chromic acid with=A-steroids.

These steroids belong to the cyclopentanop'olyhy'drophenanthrene or thepolyhydrochrysene:series. =Partic-\1- lar importance is attached to thederivatives 0f cholestane, coprostane, sitostane, stigmastane, cholane,allocholane, in addition to may have otherxlouble-bonds. Where anydouble-bonds are reactivethese are: suitably protected before ttheoxidation step of the process, for example by attachment of halogen orhydrogen halide. For the protection of the 5,6-double bond, M' -steroidsmay be converted into i-steroids. They can be obtained, e. g. from thecorresponding A -compounds by dehydrogenation with mercuric acetate,selenium dioxide or bromine.

For the oxidation according to the invention, chromic acid is used inthe presence of a diluent, such as an organic solvent, such as benzeneor glacial acetic acid.

The following examples illustrate the invention, the relation betweenparts by weight and parts by volume being the same as that between thegram and the cubic centimeter:

Example 1 6 parts by weight of A -3fi-acetoxy-ergostatriene aredissolved in 500 parts by volume of glacial acetic acid and 3 parts byweight of chromic acid, dissolved in 100 parts by volume of 90 per centacetic acid, are slowly dropped in while stirring. Stirring is continuedfor one hour at the end of which time all the oxidizing agent isconsumed. The reaction mixture is diluted with water, extracted withether and the ethereal solution worked up in the usual way. From thecrude product there is obtained by crystallization from methanol A-3,B-acetoxy-7oxo-ergostadiene in nice crystals of melting point 176178C. [a] =-58 (in chloroform). This substance has no characteristicabsorption band in the ultraviolet spectrum.

If A -3-;3-acetoxy-stigmastatriene is treated with chromic acid underthe same conditions A 3fi-acetoxy-7-oxo-stigmastadiene is obtained.

Example 2 1 part by weight of A -3fl,20-diacetoxy-allo-pregnadiene isdissolved in parts by volume of glacial acetic acid and transferred intoa three-necked flask equipped with a thermometer, a dropping funnel andan.

efricient stirrer. A solution of 0.5 part by weight of chromic acid in15 parts by volume of per cent acetic acid is then slowly dropped intothe well stirred solution, which is kept at +17 C. by cooling in a waterbath. After the addition is complete, stirring is continued for onehour, during which time all the oxidizing agent is consumed. Thereaction mixture is then worked up by diluting with ether, washing theethereal solution with water, sodium bicarbonate solution and water,drying and evaporating. From the crude reaction product A35,20-diacetoxy-7-oxo-allo-pregnene can be isolated by crystallizationfrom a mixture of acetone and water or ether and hexane. In theultraviolet spectrum this product only shows end absorption at low wavelength.

By oxidizing A' -3fi,17 8-diacetoxy-androstadiene in an analogous mannerM -3,6,17p-diacetoxy-7oxo-andro- Example 3 0.6 part by weight of methylA' -3a-acetoxy-choladienate is dissolved in 10 parts by volume ofbenzene. 50 parts by volume of acetic acid are added and 0.3 part byweight of chromic acid dissolved in 10 parts by volume of 90 per centacetic acid are slowly dropped into the well stirred benzene-acetic acidsolution at room temperature. The reaction mixture is stirred for aperiod of 2 hours and then Worked up exactly as described in Example 2.There is obtained a slightly yellow residue, from which methyl A-3a-acetoxy-7-oxo-cholenate is obtained by crystallization from amixture of acetone and hexane or ether and hexane.

What is claimed is:

1. A process for the conversion of a member selected from the groupconsisting of A -3-lower alkylcarbonyloxy-ergostadienes, A -3-loweralkylcarbonyloxy-stigmastadienes, A -3-loweralkylcarbonyloxyallo-pregnadienes, A -3-loweralkylcarbonyloxy-androstadienes, A' -loweralkylcarbonyloxy-cholestadicues and A' -3-loweralkylcarbonyloxy-choladienes to the corresponding A -3-loweralkylcarbonyloxy-7- oxo-compounds, which comprises subjecting the saidmember of the said group to the action of chromic acid.

2. A process for the conversion of a lower alkyl A -3-loweralkylcarbonyloxy-choladienate to the corresponding lower alkyl A-3-lower alkylcarbonyloxy- 7-oxo-cholenate, which comprises subjectingthe lower alkyl A -3-lower alkylcarbonyloxy-choladienate to the actionof chromic acid.

3. A process for the conversion of methyl A -3aacetoxy-choladienate tothe corresponding methyl A 3a-acetoxy-I-oxo-cholenate, which comprisessubjecting the methyl A -3a-acetoxy-choladienate to the action ofchromic acid.

References Cited in the file of this patent Fieser et al.: NaturalProducts Related to Phenanthrene, 3rd ed., p. 425 (1949), and pp.282-85.

1. A PROCESS FOR THE CONVERSION OF A MEMBER SELECTED FROM THE GROUPSCONSISTING OF $7,8;9,11-3-LOWER ALKYLCARBONYLOXY-ERGOSTADIENES,$7,8;9,11-3-LOWER ALKYLCARBONYLOXY-STIGMASTADIENES, $7,8,9,11-3-LOWERALKYLCARBONYLOXYALLO-PREGNADIENES, $7,8,9,11-3-LOWERALKYLCARBONYLOXY-ANDROSTADIENES, $7,8:9,11-LOWERALKYLCARBONYLOXY-CHOLESTADIENES AND $7,8:9,11-3-LOWERALKYLCARBONYLOXY-CHLORADIENES TO THE CORRESPONDING $9,11-3-LOWERALKYLCARBONYLOXY-7OXO-COMPOUNDS, WHICH COMPRISES SUBJECTING THE SAIDMEMBER OF THE SAID GROUP TO THE ACTION OF CHROMIC ACID.